In order to identify genetic determinants of alcoholism we have focused on human and murine behaviors that are associated with serotonin function. Serotonin synthesis is controlled by the activity of the enzyme tryptophan hydroxylase (TrH). TrH is the rate-limiting enzyme in the production of this neurotransmitter. Therefore, we hypothesize that control of the TrH gene expression and genetic variants of TrH play a major role in the etiology of serotonin-associated behaviors. We have cloned and sequenced the cDNA and gene coding for murine TrH. The TrH gene was located to chromosome 7. Cloning and sequencing of this gene also allowed the characterization of its putative regulatory region as well as its intron/exon boundaries. We are extending these studies to investigate the factors and DNA sequences controlling the expression of this gene. Allelic variants of the TrH gene have been identified by SSCP analysis in both humans and mice. Utilizing the CEPH families, we are mapping the tryptophan hydroxylase gene in the human genome. We are studying the relationship of this polymorphism to impulsive behavior in impulsive and alcoholic Finns. In recombinant LSXSS inbred strains of mice, alcohol induced sleep time showed a significant association with the TrH DNA polymorphism. DNA constructions are being produced that will be inserted into the genome of mice. These studies and those on natural genetic variants of TrH will be used to quantitate the serotonergic component of behavior as well as to determine the DNA sequences required for tissue specific gene expression.